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CySBGN Tutorial
Table of contents TABLE OF CONTENTS ..................................................................................................................... 1 INTRODUCTION ............................................................................................................................... 2 HOW TO DOWNLOAD AND INSTALL CYSBGN ........................................................................ 3 FROM THE WEBPAGE ......................................................................................................................................... 3 FROM CYTOSCAPE .............................................................................................................................................. 3 INSTALLING CYSBGN DEPENDENCIES ........................................................................................................... 4
HOW TO IMPORT A SBGN DIAGRAM ......................................................................................... 5 HOW TO GENERATE A SBGN DIAGRAM FROM A SBML FILE ............................................. 6 BIOMODELS DATABASE ................................................................................................................................... 7 HOW TO DOWNLOAD SBML MODELS FROM BIOMODELS ......................................................................... 7 HOW TO GENERATE SBGN DIAGRAM FROM SBML MODELS .................................................................... 9 HOW TO IMPORT THE SBML MODELS INTO CYTOSCAPE ........................................................................ 10
HOW TO SIMPLIFY A SBGN DIAGRAM ................................................................................... 11 HOW TO VALIDATE A SBGN-‐ML FILE ..................................................................................... 13 CYSBGN INTERACTING WITH CYTOSCAPE FEATURES ..................................................... 14 SHORTEST PATH IN A METABOLIC PATHWAY ............................................................................................ 14 NETWORK MOTIFS DISCOVERY ..................................................................................................................... 18
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Introduction CySBGN allows Cytoscape users to import, validate and export the layout of SBGN diagrams stored in SBGN-‐ML format. This plug-‐in extends Cytoscape features to SBGN diagrams as shown in the last section of this tutorial. CySBGN dependencies are:
o LibSBGN allows CySBGN to read, query, save and validate SBGN-‐ML files.
o CySBML is necessary for the automated conversion of SBML into SBGN, where CySBML is used to import SBML models into Cytoscape.
o SBFC stands for Systems Biology Format Converter and is also vital for
the automated generation of SBGN diagram form a SBML model. SBFC is responsible to convert the SBML model file into a SBGN-‐ML file.
CySBGN is developed in Java and it is available under GNU GPL v3 license. Further information is available on plug-‐in’s webpage www.ebi.ac.uk/saezrodriguez/cysbgn/
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How to download and install CySBGN CySBGN can be downloaded and installed from its webpage or directly within Cytoscape using Plugins Manager. Cytoscape recommended version: Cytoscape v2.8.3
From the webpage
1. Download CySBGN from http://www.ebi.ac.uk/saezrodriguez/cysbgn/
2. Save the CySBGN-‐vX.X.jar in Cytoscape plugins folder. By default is: a. Windows: “C:\Program Files\Cytoscape-‐v2.x.x\plugins\” b. Mac OS: “/Applications/Cytoscape-‐v2.x.x/plugins/
3. Restart Cytoscape.
From Cytoscape Within Cytoscape:
1. Go to Plugins Manager
2. Search for CySBGN and click Install button
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Installing CySBGN dependencies The last step in CySBGN installation is to install its dependencies. CySBGN requires CySBML to allow the automated conversion of SBML files into SBGN diagrams.
1. The fully supported version of CySBML can be downloaded in CySBGN webpage (http://www.ebi.ac.uk/saezrodriguez/cysbgn/) in Download section.
2. Save the CySBML-‐vX.X.jar in Cytoscape plugins folder. By default is: a. Windows: “C:\Program Files\Cytoscape-‐v2.x.x\plugins\” b. Mac OS: “/Applications/Cytoscape-‐v2.x.x/plugins/
3. Remove sbml-‐reader-‐2.8.X-‐jar-‐with-‐dependencies.jar file in Cytoscape
plugins folder
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How to import a SBGN diagram After CySBGN is installed the user can import a SBGN diagram by clicking in File -‐> Import -‐> Network (Multiple File Types) and then select the respective SBGN-‐ML file.
Note: Example SBGN-‐ML files can be found and downloaded in the following link: http://sourceforge.net/projects/cysbgn/files/SBGN-‐ML_Example_Files/
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How to generate a SBGN diagram from a SBML file CySBGN allows to automatically generate SBGN diagrams from SBML models by making use of CySBML plug-‐in and SBFC converter. Once CySBGN is fully installed (CySBGN and CySBML) the user can select a SBML model, then CySBGN uses SBFC to convert the selected SBML file into a SBGN-‐ML file.
Note: The conversion process may take a while
After the conversion the SBGN diagram visualization is integrated with the information made available by CySBML plug-‐in (e.g. information contained in web databases about the selected specie is displayed in a right side panel by CySBML plug-‐in).
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BioModels Database The user can also take advantage of BioModels database as a resource of SBML models.
URL: http://www.ebi.ac.uk/biomodels-‐main/
How to download SBML models from BioModels Database
1. From BioModels main webpage (the one above) type the desired model’s name and hit Search button
a. e.g. Middleton2012_GibberellinSignalling
2. The list with the matching models is presented. To select the model click on the model’s ID
Note: Obtained model list for Middleton2012_GibberellinSignalling search
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3. The user can then visualise detailed information about the model or download it in SBML format.
a. For full support of SBFC and CySBGN we recommend, whenever possible, to download the SBML version without identifiers
URL: http://www.ebi.ac.uk/biomodels-‐main/BIOMD0000000422
4. As shown in the picture above, to get the SBML model click Download
SBML and select the appropriate version of the SBML file.
5. Save the file.
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How to generate SBGN diagrams from SBML models After installing CySBGN and CySBML plug-‐ins correctly (check How to download and install CySBGN section for detailed instructions) the user can complement SBML model visualisation with an automated generated SBGN diagram of the model.
1. Through Plugins -‐> CySBGN -‐> SBML to SBGN… the user can select a SBML model and generate the respective SBGN diagram.
a. The conversion process may take awhile
Note: Since we are dealing with automated generation of diagrams the layout may need some manual correction. Here the overlapping nodes were moved to
be completely visible. SBML model link: http://www.ebi.ac.uk/saezrodriguez/cysbgn/files/BIOMD0000000422.xml
2. Selected node information is visible in the Results Panel (right side panel)
in CySBML tab, also Data Panel (bottom panel) shows SBML and SBGN node’s attributes.
a. Some attributes may be hidden. Click Select All Attributes ( ) button to visualise all the attributes
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How to import the SBML models into Cytoscape Before importing the SBML model in Cytoscape, check if CySBML plug-‐in is correctly installed (check How to download and install CySBGN section for detailed instructions in process is analogous).
1. After CySBML is installed the user can import a SBML model by clicking in File -‐> Import -‐> Network (Multiple File Types) and then select the respective SBML file.
Note: This is how Cytoscape should look like when importing the selected model
in the previous steps using CySBML. SBML model link: http://www.ebi.ac.uk/saezrodriguez/cysbgn/files/BIOMD0000000422.xml
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How to simplify a SBGN diagram To render the diagrams as close as possible to the original, CySBGN creates some auxiliary nodes and edges to overlap the Cytoscape rendering restrictions (e.g. invisible ports to allow a edge to connect with another edge). Although, this auxiliary shapes represent some limitations to the correct operability of Cytoscape analysis or display methods (e.g. in a shortest path algorithm the auxiliary nodes are considered as one step as well). To overcome this a simplification method was available allowing to remove displaying auxiliary shapes, SBGN complex or compartments entities. The image below shows how a user can preform the simplification of a previously imported SBGN diagram.
1. Import a SBGN diagram. a. Example map kinase cascade diagram (image below)
2. The user can then automatically generate a simplified version of the
diagram. Plugins -‐> CySBGN -‐> Create simplified network…
Note: Link for the SBGN-‐ML file
http://sourceforge.net/projects/cysbgn/files/SBGN-‐ML_Example_Files/mapk_cascade.sbgn/download
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3. After the simplification process the simplified network can be seen side-‐by-‐side with the original SBGN diagram.
4. Analysis methods or layout algorithms can be applied to the simplified network.
Note: After applying the yFiles hierarchical layout manual modifications were
done of obtain a better visualisation.
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How to validate a SBGN-‐ML file CySBGN allows users to perform a syntactic validation of SBGN-‐ML documents using libSBGN. The validation function is accessible under the CySBGN menu in the Plugins menu and runs a syntax validation of the SBGN-‐ML file used to import currently selected SBGN-‐ML diagram.
1. The user can select the SBGN-‐ML to validate through Plugins -‐> CySBGN -‐> Validate Network SBGN-‐ML …
2. Any issue found with the SBGN-‐ML file is listed in the Data Panel (bottom panel) in the CySBGN-‐Validation tab. Selecting the issue from the list will highlight the correspondent arc or node.
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CySBGN extending Cytoscape features to SBGN diagrams
Shortest path in a metabolic pathway A simple example of the interaction of CySBGN with other Cytoscape plug-‐ins is for instance the use CytoHubba plug-‐in to detect the shortest path between two metabolites in a metabolic network.
1. Install CytoHubba plug-‐in through Cytoscape Plugins Manger a. Check How to download and install CySBGN for more details
2. Import a SBGN metabolic network
a. e.g. Central plant metabolism
Note: Link for the SBGN-‐ML file
http://sourceforge.net/projects/cysbgn/files/SBGN-‐ML_Example_Files/central_plant_metabolism.sbgn/download
3. In this example we want to find the shortest path between Pyruvate and
Succinate a. After checking the network attributes (Data Panel) we know that
Pyruvate node ID is glyph595 and Succinate node ID is glyph387
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4. Before running the shortest path algorithm we need first to compute Hubba results for each node of the network. Plugins -‐> cytoHubba -‐> Compute Hubba results
5. CytoHubba will then ask the user to select the desired network and the attribute name to store the computed results.
a. Network: Central_plant_metabolism b. Attribute Name: example
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6. After the scores are computed we can now define the start and end nodes in Hubba tab in the control panel as shown below.
a. Path from Pyruvate (glyph595) to Succinate (glyph387)
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7. After adding the configurations click submit button to run the algorithm. The expected result is shown below.
Note: The SBGN layout may not be selected by default in the shortest path
network. Set SBGN visual style in VizMapper tab in the Control Panel (left side panel).
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Network motifs discovery Another example of CySBGN interoperability with other plug-‐ins is for instance the discovery of network motifs using NetMatch Cytoscape plug-‐in.
1. Install NetMatch plug-‐in through Cytoscape Plugins Manger a. Check How to download and install CySBGN for more details. b. NetMatch is not verified to work with the latest versions of
Cytoscape, although it operates correctly.
2. Import a SBGN metabolic network a. e.g. Central plant metabolism
Note: Link for the SBGN-‐ML file
http://sourceforge.net/projects/cysbgn/files/SBGN-‐ML_Example_Files/central_plant_metabolism.sbgn/download
3. Start NetMatch by clicking in NetMatch menu under Plugins. See image
below.
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4. Now NetMatch tab should be visible in Control Panel (left side panel). Click Draw a Query (pencil icon) to draw the desired motif to search in the network.
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5. In this case (image below) we are looking for a motif that represents a metabolite that can be converted into another using one enzyme, and the other way around by another different enzyme. After defining the motif click Pass Query to NetMatch button.
6. Click Match button in the bottom part of NetMatch tab in Control Panel.
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7. At this point NetMatch should have found some matches to the motif defined before. The matching motifs are listed in the Result Panel (right side of the window).
Note: Here is highlighted the reversible transformation of oxaloacetate to PEP
using different enzymes.
